IDDF2018-ABS-0178 Construction of colorectal cancer subtypes based on stroma-specific gene expression and prediction of drug response

Abstract

Background Gene expression profiling has been used to classify molecular subtypes in colorectal cancer (CRC). Given that tumour transcriptome signals not only derive from cancer cells but also from tumour microenvironment. Recent studies have shown that noncancerous components might affect the classification of CRC subtypes. We hypothesised that using stroma-specific gene signature would be more effective to identify CRC subtypes with clinical relevance. Methods To this end, we analysed gene expression profiles from 1821 CRCs. We firstly constructed a signature where genes were both stroma-specifically expressed and associated with drug response. Further, we identified CRC stroma-specific subtypes (CRSS) using K-means clustering based on the signature and verified the classification in two datasets. We also used the nearest template prediction algorithm to predict drug response. Results The CRSS subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics and specific enrichments of gene signatures and signalling pathways (table 1): (i) CRSS-A: non-serrated adenomas, colon crypt top derived, glycolytic, epithelial, KRAS-mutant, sensitive to Cetuximab, enriched with NK cells; (ii) CRSS-B: non-serrated adenomas, colon crypt base derived, DNA replication activity, epithelial, BRAF wild-type, TP53 mutant, chromosomal stability, distal CRC, sensitive to Cetuximab; (iii) CRSS-C: serrated adenomas, colon crypt top derived, interleukin-6 pathway activity, epithelial, microsatellite instability (MSI), BRAF mutant, hypermutation, chromosomal instability, CpG island methylator phenotype, proximal CRC, sensitive to Gefitinib, good prognosis, enriched with cytotoxic lymphocytes and monocytic lineage; (iv) CRSS-D: non-serrated adenomas, colon crypt top derived, interleukin-2 pathway activity, epithelial-mesenchymal transition (EMT), chromosomal stability, sensitive to FOLFIRI and FOLFOX chemotherapy regimens; (v) CRSS-E: serrated adenomas, colon crypt base derived, EMT, immune pathways activation, poor prognosis, sensitive to FOLFIRI and FOLFOX, enriched with endothelial cells and fibroblasts; (vi) CRSS-F: serrated adenomas, colon crypt base derived, EMT, IGF1 pathway activity, poor prognosis, sensitive to FOLFIRI and FOLFOX, enriched with endothelial cells, fibroblasts and monocytic lineage. Conclusions We classified CRC into six molecular subtypes (CRSS). The identification of CRSS subtypes is critical, as it provides possibilities to identify robust prognostic models and provide more precise therapeutic options for each CRC subtype.